DOI: 10.5114/pjp.2015.

53008 Pol J Pathol 2015; 66 (2): 125-132

O riginal

paper

M ultifocal / multicentric

breast carcinomas showing

intertumoural heterogeneity : a comparis on of

histological tumour type and

N ottingham

histological

grade of primary tumour and lymph node metastasis

M onica B oros , C ristian P odoleanu , R ares G eorges cu , C osmin M oldovan , C alin M olnar ,
S imona S tolnicu

University of Medicine and Pharmacy, Targu Mures, Romania

Our study aimed to compare the histological tumour type and Nottingham histological grade of invasive tumour foci in multifocal/multicentric breast carcinomas
with those in corresponding axillary lymph node (LN) metastases.
We reassessed slides from consecutive multiple breast carcinomas surgically treated
with axillary LN dissection (2007-2012).
155 (19.23%) of 806 cases had multiple breast cancer, of which 115 (74.19%)
cases had identical morphology. Of these, 85 (73.91%) cases had axillary LN metastases morphologically identical to the originating breast tumours. 32 of the 40
(80%) cases with different morphology had axillary LN metastases; in most heterogeneous cases with differences in grade (87.5%), the grade of metastases was
identical to the grade of the tumour foci with the highest histological grade, and
in 33.33% of cases the grade in LN was concordant with the grade of smaller foci.
Among the 18 cases heterogeneous in histological type with axillary metastases,
33.33% presented heterogeneous histological types in LN, and 22.22% of them
were only concordant with the histological type of the smaller tumour foci.
The morphological aspects of axillary LN metastases correspond to the highest
histological grade and/or histological tumour type with unfavourable prognosis,
which does not necessarily appear in the largest tumour focus.
Key words: heterogeneity, lymph node metastases, multiple breast carcinoma.

Introduction
The incidence of multiple breast carcinomas varies considerably in the literature (6-77%) [1,2]. This
is due to the implementation of different definitions
and selection criteria, as well as to the interpretation of preoperative diagnostic methods [3]. There is
apositive correlation between the presence of axillary
lymph node metastases and the number of tumour
foci [4, 5]. In multiple carcinomas, between 3% and
37.5% of cases may have different histological tumour types and/or histological grades (inter-tumour
heterogeneity) [3, 6-10]. This is related to shorter

survival and may influence the choice of therapy [6].

There are older studies published in English literature concerning the impact of the morphological/
immunohistochemical features of unifocal/multiple
tumour foci on the morphological/immunohistochemical features of lymph node metastases [11, 12].
However, as far as we know, no studies have been
published on the comparison of histological tumour
type and Nottingham histological grade of primary tumour and lymph node metastases in multiple
breast carcinomas. The aim of our study was to assess
the histological features of axillary lymph node metastases and correlate them with those of the primary

125

Monica Boros, Cristian Podoleanu, Rares Georgescu, et al.

foci in multiple breast carcinomas. We believe that

this approach has prognostic and therapeutic value.

Material and methods

This study included a series of consecutive cases diagnosed with breast carcinoma between 2007
and 2012 in Tirgu Mures, Romania, originating in
a population that had not been previously screened
for breast carcinoma, since anational screening programme concerning this disease is not available in
our country. For sampling, we used the MD Anderson, Houston, USA method, consisting in a correlation between preoperative radiologic appearance
(ultrasound, mammography, MRI), a radiographic
re-examination of the serial sections performed during sampling, a comparison between intraoperative
mammography and gross examination and very detailed sampling of all suspected tumour/areas (on
conventional small blocks) [13]. Multiple invasive
breast carcinoma was defined as at least two histologically confirmed invasive tumour foci separated
from each other by uninvolved breast tissue, containing normal tissue, benign lesions and/or in situ carcinoma, regardless of the distance between the foci,
in the same or in a different quadrant [14]. Multiple foci were previously identified either by imaging
and/or by gross examination. The primary surgical
treatment consisted of modified radical mastectomy associated with axillary lymph node dissections.
No cases with lumpectomy were accepted in the
study and in none of the cases was sentinel lymph
node biopsy performed. We excluded all cases treated prior to surgery with chemotherapy and cases of
multiple in situ carcinomas. According to the guidelines used by the Oncological Department of Tirgu
Mures, patients benefited from adjuvant endocrine
therapy in ER and/or PR positive cases, as well as
anti-HER2 therapy (trastuzumab) in HER2 positive
cases. Ahigh histological grade, ahigh Ki-67 index,
and ER/PR negativity are factors that indicated the
use of chemotherapy, for at least 4 cycles over 12-16
weeks [15]. This study was approved by the Ethical
Committee of the University of Medicine and Pharmacy of Tirgu Mures, and all the procedures were
performed in compliance with relevant laws and institutional guidelines. The patients have submitted
their informed consent form for the publication of
their case details.
All microscopic slides were reviewed by two pathologists (SS, MB). The histological type of the tumour foci and of the metastases in the lymph nodes
was determined using the WHO 2012 criteria [16],
while histological grade was assessed according to the
Nottingham histological grade (NHG) in all tumour
foci (primary tumour the same grading system was
applied in all invasive carcinomas as suggested by

126

most guidelines, not only in No Special Type [NST]

ones) and lymph nodes with metastases, regardless
of the histological type of the metastases [17]. The
mixed type of infiltrating carcinoma was defined
as a tumour composed of a non-specialized pattern
(NST) representing 10-49% of the tumour, while
the rest of the tumour displayed asecond recognized
special type [16]. In this study we also designated
as mixed type the cases in which we encountered
acollision or parallel development of 2 different tumour types (excepting the NST type) in one distinct
tumour focus. This phenomenon does not represent
amixed tumour type according to WHO 2012, but
is a well-described phenomenon in the literature
[18]. Also, in every tumour focus diagnosed as NST
we looked for the presence of any minor component
of aspecial-type carcinoma associated with the NST
type, but we did not find such cases.
In all the cases studied, one tumour focus was larger than the others. We designated the largest tumour
focus as the index or 1st rank tumour, and the rest
of the foci were designated 2nd to nth rank additional
foci in the descending order of their respective sizes.
In multiple carcinomas, we individually reported the
histological tumour type and Nottingham histological grade of each tumour focus. We also reported the
number of lymph nodes involved by macrometastases
(larger than 2 mm) or micrometastases (with adiameter between 2 and 0.2 mm) and the total number of
lymph nodes analysed. All the axillary lymph nodes
were processed by sectioning them into 2 mm thick
samples that were paraffin embedded and stained
with haematoxylin and eosin (HE). In each case, we
identified and compared the histological type and
grade of the lymph node metastases to the histological type and grade of the primary multiple breast tumour foci. Amismatch was defined as at least 1 additional tumour focus displaying differences compared
to the largest focus in histological type and/or grade.
In cases with more than one metastatic lymph node,
we assessed the concordance between the histological
appearances and grades of different lymph nodes.
Statistical analysis was performed with MedCalc
(MedCalc Software, Ostend, Belgium). Fishers exact
test was used when comparing frequencies between
groups. Chi-square test was used to assess the association between the percentages of cases with lymph
node metastases in homogeneous tumours versus
heterogeneous tumours. Ap-value < 0.05 was considered statistically significant.

Results
This study initially included 806 consecutive cases
diagnosed with breast carcinomas. After the exclusion criteria were applied, only 155 cases were diagnosed as multiple carcinomas between 2007 and

Intertumoural heterogeneity of breast cancer

2012. 117 (75.48%) of the multiple carcinoma cases

had axillary lymph node metastases. Out of the 155
multiple carcinomas, 115 (74.19%) cases displayed
identical histological type and grade in all foci, while
40 (25.81%) cases showed morphological heterogeneity; of these 40 cases, 11 (7.09%) showed mismatches only between the histological tumour type
of the multiple tumour foci, 16 (10.32%) showed
mismatches only between histological grade and 13
(8.38%) cases presented with mismatches between
histological type and grade (see Table I).
Analysis of cases with identical histological type
and grade
Of the cases with identical histological type and
grade, we assessed 72 cases with 2 foci, 22 cases with
3 foci and 21 cases with 4 foci or more, with atotal
of 331 analysed tumour foci. The most frequently
encountered histological type was NST (80/115 cases) (69.56%), while special histological subtypes only
accounted for 30.43% (35/115 cases), as follows: lobular carcinoma (19 cases), carcinoma with apocrine
differentiation (13 cases) and mucinous carcinoma
(1 case). Out of the cases with identical histological type and grade, grade G3 was seen in 49 cases
(42.6%), G2 in 59 cases (51.3%), and only 6.1%
(7/115 cases) displayed grade G1.
73.91% (85 out of 115) of the cases with multiple carcinoma showing identical histological type and
grade had axillary lymph node metastases, compared
with 80% (32 out of 40) of the cases with mismatches
between histological type, grade or both (not statistically significant, p = 0.525; OR = 1.415; 95% CI:
0.585-3.403) (see Table I).
Cases with identical histological type and grade
foci displayed the same histological type and grade
in the metastases involving axillary lymph nodes, regardless of the number of foci, whereas in cases with
different histological type and grade of the primary
tumour foci lymph node metastases were heterogeneous.

and mixed type carcinoma (both types appeared in

11 tumour foci, respectively) (8.33%) (Table II).
Analysis of heterogeneous cases with metastases
32 (80%) of the 40 heterogeneous multiple breast
carcinomas determined axillary lymph node metastases, as follows: 14 (87.5%) of 16 cases with grade
mismatches, 8 (72.73%) of 11 cases with histological
type mismatches and 10 (76.92%) of 13 cases with
histological type and grade mismatches.
Of the cases in which only grade mismatches appeared (but which had the same histological type)
and which determined axillary lymph node metastases (14/16 cases), the metastases had the same histological features as the multiple breast tumours. The
histological grade of the metastases was identical
to that of the highest-grade tumour in all cases. In
35.72% (5/14 cases), the grade of the metastases was
identical to the grade of asmaller tumour than the
index tumour.
Regarding cases in which only histological type
mismatches appeared (but which had identical
grades) and which had axillary lymph node metastases (8/11 cases), the histological type of the metastases was homogeneous in 4 cases (regardless of the
number of metastases), but in the other 4 cases the
histological type was heterogeneous (see Table II).
When one of the foci was of mixed type, the mixed
aspect was mirrored in the lymph node metastases in
5 of 9 cases (e.g. micropapillary + NST, mucinous
+ NST, NST + lobular, NST + micropapillary +
mucinous) (Figs. 1, 2).
In most (7) of the 10 cases that displayed both histological type and grade heterogeneity and had metastases, the morphological appearance of the lymph
node metastases was similar to that of the index tumour. However, in 30% (3/10 cases), the metastasis

Analysis of cases with histological type and/or

grade heterogeneity
The 40 (25.81%) cases with histological type and/
or grade heterogeneity had atotal of 132 examined
tumour foci (19 cases had 2 foci, 9 cases had 3 foci,
and 12 cases had 4 foci or more). The predominant histological grade of the tumour foci was G3
(64/132 foci) (48.48%), followed by G2 (61/132 foci)
(46.21%), and only 7 foci (5.3%) exhibited grade G1.
In these heterogeneous cases (in which mismatches
between the histological type and/or grade of the foci
were encountered), the most frequent histological
types were: NST (78/132 foci) (59.09%), followed by
micropapillary type (16/132 foci) (12.12%), lobular

Fig. 1. Axillary lymph node metastasis with mixed histological type (lobular + NST) (also found in the 1st rank
tumour); HE, magnification 4

127

Monica Boros, Cristian Podoleanu, Rares Georgescu, et al.

Fig. 2. Axillary lymph node metastasis displaying three

different histological types in the metastasis (micropapillary in the lower middle, NST in the upper left and mucinous carcinoma in the upper right of the image); HE,
magnification 4

was most likely determined by additional tumour

foci and the metastases in lymph nodes displayed
the histological type and grade of these smaller foci;
all these multiple metastases had an identical histological type and grade, which was similar to one of
the additional foci. The histological grade found in
the lymph node metastases was similar to that of the
highest-grade tumour focus in 8 of these 10 cases;
only in 2 cases did the metastases have alower grade.
Also in this group, the histological type of the axillary
lymph node metastases was heterogeneous in 2 cases
(20%) (see Table I, II).
The results are summarized in Table III.
Comparison between metastases
in heterogeneous tumours
One of the 32 cases analysed had asingle lymph
node metastasis (micrometastasis). In the 31 cases
with macrometastases in which more than one lymph
node was involved, we assessed the concordance between the histological appearances of the metastases.
In 25 cases (80.64%) all the lymph nodes involved
displayed the same histological type, whereas in 6
cases (19.35%) different lymph nodes had different
histological types.

Discussion
One of the most important prognostic factors in
breast carcinoma is the axillary lymph node status,
i.e. the presence or absence of axillary metastases [16,
19]. Disease-free survival and overall survival decrease proportionally with the increase of the number
of positive axillary lymph nodes [16]. Most studies
reveal an increased rate of metastases in multiple car-

128

cinomas when compared to unifocal carcinomas [2-5,

7, 9, 20-22] (Table IV).
Aseries of factors are known to predict the presence of axillary metastases: larger tumour size, presence of lymphovascular invasion, grade 3 tumour,
tumours with lateral or retro-areolar localization,
molecular status, as well as the number of tumour
foci [15, 16, 24-26]. However, the predictive role of
patient age and histological subtype remains controversial [27, 28].
There are histological subtypes with excellent
prognosis: tubular carcinoma, cribriform carcinoma,
adenoid-cystic carcinoma, pure mucinous carcinoma [16], as well as subtypes associated with aworse
prognosis, frequently diagnosed in ametastatic stage:
micropapillary carcinoma, inflammatory carcinoma,
NST carcinoma, lobular carcinoma [16, 29, 30]. Our
study revealed that, when present in association with
heterogeneous primary tumours, axillary lymph node
metastases may present heterogeneous histological
types (in 33.33% of cases). Usually, these metastases
display the histological features of the index tumour,
but may also display the histological features of the
tumour known to have an unfavourable prognosis
(such as micropapillary or NST type). In this series,
in 4 out of 18 cases with different histological type
(22.22%) the histological type of the metastases was
only concordant with the histological type of the
smaller tumour focus.
Histological grade is aknown prognostic factor in
breast carcinomas, as numerous studies have proved
its significant association with survival [16, 31]. At
the same time, it is an important component of the
therapeutic decision and has apredictive role in therapy response [15, 32, 33]. In our study, in most heterogeneous cases with differences in grade (21/24)
(87.5%), the metastases had identical grade as the
tumour with the highest histological grade, usually
G3, and in 8 out of 24 (33.33%) cases the grade in
LN was concordant with the grade of smaller foci.
Clinical decisions in systemic adjuvant therapy
in breast cancer are based on the histological criteria and on the immunohistochemical profile of the
largest tumour focus, ignoring those of the smaller
simultaneous cancer [15, 32, 33]. In our study, in
all 80 cases with axillary lymph node metastases and
identical histological type/grade, the lymph nodes
displayed identical histology and grade to the primary tumours. However, in 22.2% (4/18) of cases with
different histological type, the lymph node metastases had the features (histological type and grade) of
the smaller additional tumour and, in 33.33% (8/24)
of cases that displayed only grade heterogeneity, the
grade of the metastases was similar to the grade of
an additional focus. Strictly observing the recommendations of the European Guidelines for Quality
Assurance in Breast Cancer Screening and Diagno-

Total

39

37

11

18

16

11

13

NSTG1

NSTG2

NSTG3

MUCG1

APOG2

APOG3

LOBG2

LOBG3

DG

DH

DG and
DH

2 foci

11

20

26

26

16

24

25

3 foci

12

4 foci
1

21

10

24

33

16

25

18

16

21

12

26

59

N0 N1 N2 N3

NST G1
1

NSTG2
1

31

16

10

21

35

10

32

27

12

16

10

21

47

MU G1

AP G2

11

DHG2

DHG3
1

DH, DG

n number of tumour foci; cc carcinoma; ALNM axillary lymph node metastasis; DG different histological grade between tumour foci (grade heterogeneity); DH different histological type between tumour foci (histological type heterogeneity); G1, G2 and G3 Nottingham histological grade; NST Invasive carcinoma of no special type; ILC invasive lobular carcinoma; MET metaplastic carcinoma; APO carcinoma with apocrine differentiation; MIC invasive micropapillary carcinoma; MIX 2 different tumour types in one distinct tumour focus; MU mucinous carcinoma; NEU carcinoma with neuroendocrine differentiation

Histological
type
and
grade in
tumours

25

59

N2

33

N1

N3

38

32

4 foci

N0

32

3 foci

Lymph
node
status

91

2 foci

Number
of foci

Parameter

155/117

Category

Total cc

ALNM

cc with

AP G3

Histological type and grade in lymph node metastases

LO G2

status

LO G3

Lymph node
MET G2

foci

MIC G3

Number of

NEU

Total N
(%)
NSTG3

Table I. Clinico-pathological characteristics of 155 multiple breast carcinomas and axillary lymph node metastases

Intertumoural heterogeneity of breast cancer

129

Monica Boros, Cristian Podoleanu, Rares Georgescu, et al.

Table II. Summary of 40 cases with heterogeneous multiple breast carcinomas, with discordances/mismatches between
histological types and grades of multiple tumours and the morphology of lymph nodes
Case
no.

No. of

Histological type in

NHG in multiple

foci

multiple breast tumours

tumour foci

status

Histological
type in LNM

NHG in
LNM

MIX/NST

3/1

N2

NST

NST/APO

2/3

N1

APO

MIC/NST

3/2

N2

NST

APO/NST

3/2

N3

APO, NST

3, 2

ILC/MIC

2/3

N3

MIC

NEU/NST/NST

2/3/2

N1a

NEU

ILC/ILC/NST

2/2/3

N3

NST

MIX/MIC/NST

3/3/2

N1

MIX, NST

NST/MIC/NST

3/3/2

N1

NST

10

MIX/MIX/ILC/ILC/ILC

3/3/2/2/2

N3

NST

11

APO/NST

3/1

N0

12

MUC/NST/MUC

2/2/1

N0

13

NST/MET/NST

3/2/3

N0

14

MIX/MUC

3/3

N3

NST, MUC

15

NST/MIX

2/2

N2

NST

16

MIX/ILC

2/2

N3

MIX, ILC

17

APO/NST/NST/NST/NST

3/3/3/3/3

N3

APO, NST

18

MIX/NST/NST/NST/NST

2/2/2/2/2

N2

NST

19

APO/MIC/MIC/MIC/APO

3/3/3/3/3

N3

APO

20

MIX/NST/MIC/MIC/MIC/MIX/MIC

3/3/3/3/3/3/3

N3

NST

21

MIC/NST/MIC/MIC/MUC/MIC/MIC

3/3/3/3/3/3/3

N2

MIC, NST,
MIX

22

APO/NST

3/3

N0

23

APO/NST

3/3

N0

24

MIX/NST/NST

2/2/2

N0

25

MET

2/3

N2

MET

26

NST

3/2

N1

NST

27

NST

2/3

N1

NST

28

NST

2/3

N1

NST

29

NST

2/1

N2

NST

30

ILC

2/3

N3

ILC

31

NST

3/3/2

N2

NST

32

NST

3/2/2

N3

NST

33

NST

3/3/2/3

N3

NST

34

NST

3/2/3/2

N3

NST

35

NST

2/1/2/1

N1

NST

36

NST

3/2/2/2

N3

NST

37

NST

2/3/2/2/2/2

N3

NST

38

11

NST

3/2/2/3/2/2/2/2/2/2/2

N3

NST

39

ILC

2/3

N0

40

NST

1/2

N0

11 cases with mismatch in histological type (inter-tumour heterogeneity in histological type) marked with yellow;
16 cases with mismatch in histological grade between tumoural foci (intertumoural heterogeneity in histological grade) marked with purple;
13 cases with mismatch in both histological type AND grade marked with blue
NHG Nottingham histological grade; LNM lymph node metastases; NST invasive carcinoma of no special type; ILC invasive lobular carcinoma; MET metaplastic carcinoma; APO carcinoma with apocrine differentiation; MIC invasive micropapillary carcinoma; MIX 2 different tumour types in one distinct tumour
focus; MUC mucinous carcinoma; NEU carcinoma with neuroendocrine differentiation

Intertumoural heterogeneity of breast cancer

Table III. Summary of heterogeneous multiple breast carcinomas and their axillary lymph node metastases
Total

Total
(N, %)

ALNM
(N, %)

Cases with
inter-tu-

Cases with grade

heterogeneity in

mour grade
heteroge-

(DG),
with ALNM
24
neity

155

117
(75.48%)
85
(73.91%)

Cases with identical

115
histological type and
(74.19%)
grade
Cases with inter-tu40
32 (80%)
mour heterogeneity
(25.80%)
Mismatches between
16
14 (87.5%)
histological grade (DG) (10.32%)
Mismatches between
11 (7.09%) 8 (72.73%)
histological type (DH)
Mismatches between
13 (8.38%)
10
histological type AND
(76.92%)
grade (DG, DH)

which the

ALNM

Cases with
histological type

Cases in
ALNM
display histo-

neity with

heterogeneity

heteroge-

is similar in grade
with smaller, ad-

which

logical type

8 (33.33%)

ALNM
18

24

8 (33.33%)

18

6 (33.33%)

14

5 (35.7%)

4 (50%)

10

3 (30%)

10

2 (20%)

ditional tumours

6 (33.33%)

ALNM axillary lymph node metastases; DG different histological grade between tumour foci; DH different histological type between tumour foci

Table IV. Comparative lymph node involvement (LNI) in invasive multiple (M) and unifocal (UF) breast carcinoma (BC)
Authors

Number of cases

LNI in MBC (%)

LNI in UFBC (%)

p-value

Andea et al. [7]

570

69.3

54.5

0.0009

Coombs et al. [20]

848

52.1

37.5

0.009

Cabioglu et al. [5]

1322

58.5

42

< 0.0001

25.320

48.6

39

< 0.001

Tot [23]

519

53

20

< 0.0005

Weissenbacher et al. [21]

576

51.7

41.7

0.0001

Rezo et al. [22]

812

49.6

33.7

0.001

Moutafoff et al. [9]

1458

59.4

39.3

< 0.0001

Boros et al. [3]

418

73.62

58.71

0.01

Yerushalmi et al. [2]

sis, AJCC (2010) or TNM 2012 regarding multiple

tumours, and reporting only the histological tumour
type and NHG (Nottingham histological grade) of
the index tumour while not taking into consideration
the heterogeneous additional tumour foci may limit
the patients opportunity to benefit from appropriate
therapy [16, 19, 34].
The aim of the present study was not to prove
that particular lymph node metastatic foci originate
from a particular tumour focus in multiple breast
carcinomas (although it is likely that in these cases
more than one tumour focus, including both the additional foci and the index tumour, determined axillary lymph node metastases). This complex problem
cannot be solved in some cases even with the use of
molecular techniques (since multiple tumour foci

may have identical molecular footprints). This paper,

however, was aimed at underlining the histological
heterogeneity of multiple tumours and their metastases, proving that multiple foci are not as histologically homogeneous as assumed in current practice.
The histological features (type and grade) of axillary lymph node metastases in multiple breast carcinomas correspond to the histological type with unfavourable prognosis and/or the highest histological
grade, which is not necessarily of the largest tumour
focus. For this reason, we stress the necessity to individually report and assess each tumour focus in multiple breast carcinomas.
The authors declare no conflict of interest.

131

Monica Boros, Cristian Podoleanu, Rares Georgescu, et al.

References
1. Katz A, Strom E, Buchholtz TA, et al. The influence of pathologic tumour characteristics on loco regional recurrence rates
following mastectomy. Int J Radiat Oncol Biol Phys 2001; 50:
735-742.
2. Yerushalmi R, Kennecke H, Woods R, et al. Does multicentric/
multifocal breast cancer differ from unifocal breast cancer? An
analysis of survival and contralateral breast cancer incidence.
Breast Cancer Res Treat 2009; 117: 365-370.
3. Boros M, Marian C, Moldovan C, et al. Morphological heterogeneity of the simultaneous ispilateral invasive tumour foci in
breast carcinoma: Aretrospective study of 418 cases of carcinomas. Pathol Res Pract 2012; 208: 604-609.
4. Tot T. Clinical relevance of the distribution of the lesions in
500 consecutive breast cancer cases documented in large-format histologic sections. Cancer 2007; 110: 2551-2560.
5. Cabioglu N, Ozmen V, Kaya H, et al. Increased Lymph Node
Positivity in Multifocal and Multicentric Breast Cancer. J Am
Coll Surg 2009; 208: 67-74.
6. Pekar G, Gere M, Tarjan M, et al. Molecular phenotype of the
foci in multifocal invasive breast carcinomas: intertumoural
heterogeneity is related to shorter survival and may influence
the choice of therapy. Cancer 2014; 120: 26-34.
7. Andea AA, Wallis T, Newman LA, et al. Pathologic analysis of
tumour size and lymph node status in multifocal/multicentric
breast carcinoma. Cancer 2002; 94: 1383-1390.
8. Middleton LP, Vlastos G, Mirza NQ, et al. Multicentric Mammary Carcinoma: evidence of monoclonal proliferation. Cancer
2002; 94: 1910-1916.
9. Moutafoff C, Coutant C, Bezu C, et al. Prognostic and predictive factors in multifocal breast carcinoma. Gynecol Obstet
Fertil 2011; 39: 425-432.
10. Choi Y, Kim EJ, Seol H, et al. The hormone receptor, human
epidermal growth factor receptor 2, and molecular subtype
status of individual tumour foci in multifocal/multicentric
invasive ductal carcinoma of breast. Hum Pathol 2012; 43:
48-55.
11. Bloom HJ, Richardson WW. Histological grading and prognosis in breast cancer; astudy of 1409 cases of which 359 have
been followed for 15 years. Br J Cancer 1957; 11: 359-377.
12. Dawson PJ, Baekey PA, Clark RA. Mechanisms of multifocal
breast cancer: an immunocytochemical study. Hum Pathol
1995; 26: 965-969.
13. Huo L. Apractical approach to grossing breast specimens. Ann
Diagn Pathol 2011, 15: 291-301.
14. Tot T. The Role of Large-Format Histopathology in Assessing
Subgross Morphological Prognostic Parameters: A single Institution Report of 1000 Consecutive Breast Cancer Cases. Int
J Breast Cancer 2012; 2012: 395-415.
15. Goldhirsch A, Winer EP, Coates AS, et al. Panel members. Personalizing the treatment of women with early breast cancer:
highlights of the St Gallen International Expert Consensus on
the Primary Therapy of Early Breast Cancer 2013. Ann Oncol
2013; 24: 2206-2223.
16. Lakhani S, Ellis IO, Schnitt SJ, Tan PH, et al. WHO Classification of Tumours of the Breast. IARC Press, Lyon 2012: 10-71.
17. Ellis IO, Elston CW. Histologic grade. In: OMalley FP, Pinder
SE eds. Breast Pathology. Elsevier, Philadelphia 2006; 225233.
18. Abdel-Fatah TM1, Powe DG, Hodi Z, et al. High frequency of
coexistence of columnar cell lesions, lobular neoplasia, and low
grade ductal carcinoma in situ with invasive tubular carcinoma
and invasive lobular carcinoma. Am J Surg Pathol 2007; 31:
417-426.
19. Perry N, Broeders M, De Wolf C, et al. European Guidelines
for Quality Assurance in Breast Cancer Screening and Diagnosis, fourth edition, Office for Official Publications of the European Communities, Luxemburg 2006; 219-313.

132

20. Coombs NJ, Boyages J. Multifocal and multicentric breast

cancer: does each focus matter? J Clin Oncol 2005; 23: 74977502.
21. Weissenbacher TM, Zschage M, Janni W, et al. Multicentric
and multifocal versus unifocal breast cancer: is the tumournode-metastasis classification justified? Breast Cancer Res
Treat 2010; 122: 27-34.
22. Rezo A, Dahlstrom J, Shadbolt B, et al. Tumour size and
survival in multicentric and multifocal breast cancer. Breast
2011; 20: 259-263.
23. Tot T. The metastatic capacity of multifocal breast carcinomas:
extensive tumors versus tumors of limited extent. Hum Pathol
2009; 40: 199-205.
24. Viale G, Zurrida S, Maiorano E, et al. Predicting the status of
axillary sentinel lymph nodes in 4351 patients with invasive
breast carcinoma treated in asingle institution. Cancer 2005;
103: 492-500.
25. Patani NR, Dwek MV, Douek M. Predictors of axillary lymph
node metastasis in breast cancer: a systematic review. Eur
J Surg Oncol 2007; 33: 409-419.
26. Yoshihara E, Smeets A, Laenen A, et al. Predictors of axillary
lymph node metastases in early breast cancer and their applicability in clinical practice. Breast 2013; 22: 357-361.
27. Wildiers H, Van Calster B, van de Poll-Franse LV, et al. Relationship between age and axillary lymph node involvement in
women with breast cancer. J Clin Oncol 2009; 27: 2931-2937.
28. Vandorpe T, Smeets A, Van Calster B, et al. Lobular and
non-lobular breast cancers differ regarding axillary lymph
node metastasis: a cross-sectional study on 4292 consecutive
patients. Breast Cancer Res Treat 2011; 128: 429-435.
29. Yu JI, Choi DH, Park W, et al: Differences in prognostic factors
and patterns of failure between invasive micropapillary carcinoma and invasive ductal carcinoma of the breast: matched
case-control study. Breast 2010; 19: 231-237.
30. Pestalozzi BC, Zahrieh D, Mallon E, et al. International Breast
Cancer Study Group: Distinct clinical and prognostic features
of infiltrating lobular carcinoma of the breast: combined results of 15 International Breast Cancer Study Group clinical
trials. J Clin Oncol 2008; 26: 3006-3014.
31. Rakha EA, Reis-Filho JS, Baehner F, et al. Breast cancer prognostic classification in the molecular era: the role of histological
grade. Breast Cancer Res 2010; 12: 207.
32. Senkus E, Kyriakides S, Penault-Llorca F, et al. ESMO Guidelines Working Group. Primary breast cancer: ESMO Clinical
Practice Guidelines for diagnosis, treatment and follow-up.
Ann Oncol 2013; 24 (Suppl 6): vi7-23.
33. Carlson RW, Allred DC, Anderson BO, et al. National Comprehensive Cancer Network. Invasive breast cancer: clinical
practice guidelines in oncology. J Natl Compr Cancer Netw
2011; 9: 136-222.
34. Edge SB, Byrd DR, Compton CC, et al. American Joint Committee on Cancer (AJCC) Cancer Staging Manual, Breast, Part
VII, Seventh edition. Springer, New York 2010; 347-376.

Address for correspondence

Cristian Podoleanu PhD
University of Medicine and Pharmacy, Targu Mures, Romania
Gheorghe Marinescu street nr 38
540139 Targu Mures, Romania
e-mail: podoleanu@me.com